In recent years, a variety of peptide drugs have been researched and developed. Major advantages of peptide drugs are that they have high affinity and high specificity for target molecules and capable of protein-protein interaction inhibition that has not easily been achieved by low molecular compounds.
Peptide drugs obtained are likely to have higher specificity in interaction with target molecules than low molecular compounds due to their chemical and biological diversity and this leads to their greater physiological activity. With regard to specificity or selectivity, peptide drugs are equivalent to antibody drugs.
Peptide drugs however have a problem that similar to almost all other biopharmaceuticals, they are not so effective because they cannot penetrate cell membranes and therefore cannot reach into the cells and they are degraded in a short time because of inferiority in protease resistance to large proteins such as antibiotics.
Resolution of such a problem of peptide drugs has been investigated recently by adding various modifications to them.
The present inventors previously developed artificial aminoacylated RNA catalyst “flexizyme (flexizyme)” (for example, Non-patent Document 1). Flexizyme is an artificial RNA catalyst having aminoacyl tRNA synthetase-like activity which can link an arbitrary amino acid to an arbitrary tRNA. Using flexizyme enables a desired amino acid to be bound to a tRNA having a desired anticodon so that a genetic code table can be rewritten by making an amino acid correspond to an arbitrary codon different from that of a natural genetic code.
Codon reassignment using flexizyme makes it possible to introduce an arbitrary amino acid containing a non-proteinogenic amino acid into an arbitrary position of a peptide and thereby provide a peptide having enhanced protease resistance, cellular permeability, or affinity or specificity for a target molecule.
In recent years, on the other hand, macrocyclization of peptides has attracted attentions. Macrocyclic peptides can be found in the natural world and they are known to have stable conformation. Macrocyclic peptides are known to show specificity higher than that of small non-cyclized peptides (Non-Patent Document 2) and are expected to be an inhibitor against highly difficult targets such as molecules whose protein-protein interaction or low molecular compound binding site is unknown. Restriction by a cyclic structure is thought to improve the bioavailability of peptides or their resistance against metabolism.
In such a trend toward investigation of addition of various modifications to peptides, peptides excellent in resistance against metabolism or stability in vivo and capable of penetrating a cell membrane and targeting intracellular molecules have been demanded particularly.